We have found 2-iodo-L-histidine and 2-iodohistamine to be potent antimalarial agents against drug-resistant strains of Plasmodium falciparum. The compounds are effective in monkeys for only 48 hrs, and we have shown that inactivation may be the result of nonenzymatic deiodination by any sulfhydry1 compounds present in serum or tissue. The facts that 2-iodohistidine doe not block protein synthesis in the parasite,a nd that the corresponding 2-bromo and 2-chloro compounds are inactive, led us to speculate that the 2-iodo compound operates by plugging one or more holes in the erythrocyte membrane and, thus, deprives the parasite of nonamino acid nutrients obtained by diffusion through such holes. We have, therefore, synthesized and tested a broad range of metabolically stable analogues of the bioimidazoles, in which the ring substituents are close to iodine in size. We have developed a very specific and general method for C-2 alkylation of imidazoles. In vitro activity appears to depend on the extent to which a substituent projects from the imidazole ring, with the optimum size slightly larger than that of iodine (e.g., isopropyl). Analysis of geometry suggests that 1-alkyl derivatives may also be effective. A regiospecific synthesis was developed for 1-alkylhistidines and histamines. As anticipated, the 1-isopropyl derivatives are almost as active as 2- isopropyl. Further analysis suggests that 4-iodo-2-isohistamine and 4- iodo-1-(aminoethyl)-imidazole, in which the iodo function will be metabolically stable, should also be effective. These compounds have been submitted for testing. Drug resistance by the parasite and multidrug resistance in cancer chemotherapy both involve drug ejection by an ATP-driven G-protein pump; in both cases, resistance can be partially overcome by calcium channel blockers, suggesting that pore size is comparable for the two systems. Accordingly, a number of our active antimalarial agents have been submitted for testing to overcome multidrug resistance.